GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging.
Abstract
Aging represents one of the most complicated and highly integrated somatic processes.
Healthy aging is suggested to rely upon the coherent regulation of hormonal and neuronal
communication between the central nervous system and peripheral tissues. The hypothalamus
is one of the main structures in the body responsible for sustaining an efficient
interaction between energy balance and neurological activity and therefore likely
coordinates multiple systems in the aging process. We previously identified, in hypothalamic
and peripheral tissues, the G protein-coupled receptor kinase interacting protein
2 (GIT2) as a stress response and aging regulator. As metabolic status profoundly
affects aging trajectories, we investigated the role of GIT2 in regulating metabolic
activity. We found that genomic deletion of GIT2 alters hypothalamic transcriptomic
signatures related to diabetes and metabolic pathways. Deletion of GIT2 reduced whole
animal respiratory exchange ratios away from those related to primary glucose usage
for energy homeostasis. GIT2 knockout (GIT2KO) mice demonstrated lower insulin secretion
levels, disruption of pancreatic islet beta cell mass, elevated plasma glucose, and
insulin resistance. High-dimensionality transcriptomic signatures from islets isolated
from GIT2KO mice indicated a disruption of beta cell development. Additionally, GIT2
expression was prematurely elevated in pancreatic and hypothalamic tissues from diabetic-state
mice (db/db), compared to age-matched wild type (WT) controls, further supporting
the role of GIT2 in metabolic regulation and aging. We also found that the physical
interaction of pancreatic GIT2 with the insulin receptor and insulin receptor substrate
2 was diminished in db/db mice compared to WT mice. Therefore, GIT2 appears to exert
a multidimensional "keystone" role in regulating the aging process by coordinating
somatic responses to energy deficits.
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https://hdl.handle.net/10161/13093Published Version (Please cite this version)
10.3389/fendo.2015.00191Publication Info
Martin, Bronwen; Chadwick, Wayne; Janssens, Jonathan; Premont, Richard T; Schmalzigaug,
Robert; Becker, Kevin G; ... Maudsley, Stuart (2015). GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological
Aging. Front Endocrinol (Lausanne), 6. pp. 191. 10.3389/fendo.2015.00191. Retrieved from https://hdl.handle.net/10161/13093.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Richard Thomas Premont
Associate Professor in Medicine
Critical physiological events throughout the body are controlled by extracellular
signals from neurotransmitters and hormones acting on cell surface receptors. Receptors
transduce these signals to alter intracellular metabolism and cellular responsiveness
through heterotrimeric G protein/second messenger pathways or through small GTP-binding
protein/protein kinase cascades. The mechanisms that control the responsiveness of
target organ G protein-coupled receptors include receptor ph

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